CN1715289A - Process for preparing 4 -substituted-9-deoxo-9a-aza-9a-homoerythromycin A derivatives - Google Patents
Process for preparing 4 -substituted-9-deoxo-9a-aza-9a-homoerythromycin A derivatives Download PDFInfo
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07H—SUGARS; DERIVATIVES THEREOF; NUCLEOSIDES; NUCLEOTIDES; NUCLEIC ACIDS
- C07H17/00—Compounds containing heterocyclic radicals directly attached to hetero atoms of saccharide radicals
- C07H17/04—Heterocyclic radicals containing only oxygen as ring hetero atoms
- C07H17/08—Hetero rings containing eight or more ring members, e.g. erythromycins
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
- A61P31/04—Antibacterial agents
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P33/00—Antiparasitic agents
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P33/00—Antiparasitic agents
- A61P33/02—Antiprotozoals, e.g. for leishmaniasis, trichomoniasis, toxoplasmosis
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07H—SUGARS; DERIVATIVES THEREOF; NUCLEOSIDES; NUCLEOTIDES; NUCLEIC ACIDS
- C07H1/00—Processes for the preparation of sugar derivatives
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- Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
- Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
- Y02P—CLIMATE CHANGE MITIGATION TECHNOLOGIES IN THE PRODUCTION OR PROCESSING OF GOODS
- Y02P20/00—Technologies relating to chemical industry
- Y02P20/50—Improvements relating to the production of bulk chemicals
- Y02P20/55—Design of synthesis routes, e.g. reducing the use of auxiliary or protecting groups
Abstract
The invention relates to processes for preparing compounds of formula (3) wherein R<4> is as defined herein, and to pharmaceutically acceptable salts thereof, as well as intermediates useful in such processes. The compounds of formula (3) are intermediates in the synthesis of antibacterial agents.
Description
The application is that application number is 02808696.1, and the applying date is on 04 11st, 2002, and denomination of invention is the preparation method of " 4 " replacement-9-deoxidation-9a-azepine-9a-a-homoerythromycin A derivatives " the dividing an application of patent application.
Background technology
" preparation method of substitutive derivative (hereinafter claiming " azalactones (class) " (azalide (s))), described derivative can be used as antiseptic-germicide and the antiprotozoal of Mammals (comprising the people) and fish and birds to the present invention relates to the C-4 of 9-deoxidation-9a-azepine-9a-homoerythromycin (homoerythromycin) A.The invention still further relates to the preparation method of the stable intermediate of theme azalides, the invention still further relates to the crystal salt of intermediate in the method for preparing the theme azalides simultaneously.The invention still further relates to pharmaceutical composition, described pharmaceutical composition contains the new compound by the subject methods preparation; The invention still further relates to the infectation of bacteria of treatment Mammals, fish and birds and the method for protozoal infections, described method is by using the new compound by described subject methods preparation to Mammals, fish and the birds of the described treatment of needs.
The broad spectrum of bacteria that known macrolide antibiotics can be used in treatment Mammals, fish and birds infects and the Protozoa infection.Such microbiotic comprises the various derivatives of Erythromycin A, for example commercially available azithromycin (azithromycin), and it is at United States Patent (USP) 4,474, mentions in 768 and 4,517,359, and the full text of these two pieces of documents is hereby incorporated by.The same with other macrolide antibiotics with azithromycin, Macrocyclic lactone compounds of the present invention has potent anti-various infectation of bacteria and protozoal infections activity, and this point below will be described.
The commercial scale production of theme material azalides has some difficulties, and it includes but not limited to: productive rate is low, some synthetic intermediate instability, and have unwanted impurity.
Summary of the invention
[1] prepare the method for following formula 3 compound trifluoroacetic acid additive salt,
Comprise: the compound of handling formula 3 with trifluoroacetic acid; Crystallization goes out the acid salt that is obtained;
R wherein
4Be hydroxy-protective group.
[2] method of [1], wherein R
4Be carbobenzoxy-(Cbz).
[3] method of [1], the Virahol crystallization of wherein said acid salt.
[4] method of [1], the wherein said acid salt crystalline mixture of methylene dichloride and methyl tertiary butyl ether.
[5] the trifluoroacetic acid additive salt of following formula 3 compounds,
R wherein
4Be carbobenzoxy-(Cbz).
[6] salt of [5], it has following formula 3a structure
R wherein
4Be carbobenzoxy-(Cbz).
[7] dibenzoyl of following formula 3 compounds-D-tartrate,
R wherein
4Be carbobenzoxy-(Cbz).
The present invention relates to the method for preparation formula 1 compound or pharmaceutically acceptable salt thereof,
Comprise: formula 2 compounds
With formula HNR
8R
15Amine in containing the organic solvent of Virahol, react, temperature of reaction is at least about 40 ℃;
Wherein:
R
3For-CH
2NR
8R
15
R
8Be C
1-C
10Alkyl; With
R
15Be H or C
1-C
10Alkyl.
In the preferred embodiment of this method, R
8Be propyl group, R
15Be H.In particularly preferred embodiments, R
8Be n-propyl, R
15Be H.
In an especially preferred embodiment, organic solvent is a Virahol.
In another preferred embodiment, the present invention relates to the preparation method of formula 1a compound or pharmaceutically acceptable salt thereof:
These method through type 2 compounds and Tri N-Propyl Amine react in containing the organic solvent of Virahol, and temperature of reaction is at least about 40 ℃.In an especially preferred embodiment, described organic solvent is a Virahol.
It should be noted: except as otherwise noted, term used herein " solution " and " mixture " can use alternately, do not consider the wherein dispersion state of composition.Except as otherwise noted, phrase used herein " organic solvent that contains Virahol " refers to non-aqueous solvent or non-aqueous solvent mixture, and wherein at least a solvent is a Virahol.In this application, " formula 1 compound " comprises formula 1 compound and formula 1a compound.Formula 1a compound is the particularly preferred embodiment of formula 1 compound, and this point is applicable to all embodiments and the preferred embodiment of method described herein.
In the embodiment of described method, temperature of reaction is lower than about 95 ℃ herein; In its embodiment preferred, temperature of reaction is lower than about 80 ℃; In its preferred embodiment, temperature of reaction is about 76 ℃ of about 50-.In its particularly preferred embodiment, temperature of reaction is about 50 ℃-Yue 55 ℃.
In the preferred embodiment of described method, be reflected at herein near carrying out under the normal pressure.In this application, term " normal pressure " refers to the pressure of the atmospheric normal range of meteorology of certain sea level elevation, and term " pressurization " refers to be higher than atmospheric pressure.In another embodiment of described method, be reflected to add to depress and carry out herein.In another embodiment of the invention, can in Virahol, add triethylamine.
Except the application's preferred embodiment, formula 2 compounds and amine have reacted successfully production 1 compound in the solvent that does not contain Virahol.Therefore, the invention still further relates to the preparation method of formula 1 compound, through type 2 compounds and HNR
8R
15React in organic solvent, described organic solvent is selected from: the mixture of benzylalcohol, acetone, methyl iso-butyl ketone (MIBK), DMSO, the trimethyl carbinol, propyl carbinol, Di Iso Propyl Ether, MTBE and DMF and the combination of these solvents, wherein temperature of reaction is at least about 40 ℃.Reaction can be carried out adding to depress, but preferably carries out under about normal pressure.The Lewis acid accelerated reaction that can add in another embodiment, catalytic amount.In embodiment, lewis acidic example comprises: magnesium bromide, potassiumiodide, lithium perchlorate, magnesium perchlorate, LiBF4, pyridine hydrochloride or tetrabutylammonium iodide therein.Preferably, Lewis acid is a magnesium bromide.
In the embodiment of described method, the molar weight of amine is at least 5 times of formula 2 compound molar weights herein.In another embodiment of described method, the concentration of amine in Virahol is at least about 5 weight moles herein.In an especially preferred embodiment, the concentration of Tri N-Propyl Amine in Virahol is about 6-7 weight mole.
In an embodiment of aforesaid method, formula 2 compounds and amine reaction were at least about 24 hours.In an one embodiment preferred, the molar weight of amine is at least 5 times of formula 2 compound molar weights, and formula 2 compounds and amine reaction were at least about 24 hours.In an one preferred embodiment, about 50 ℃ to about 80 ℃ of temperature of reaction.In its preferred embodiment, the molar weight of amine is about 20 times of formula 2 compound molar weights, and the concentration of amine in Virahol is about 6 weight moles, and formula 2 compounds and amine reacted at least about 24 hours, about 50 ℃ to about 55 ℃ of temperature of reaction.
Another embodiment of method described herein also comprises the free alkali of crystallization formula 1 compound.In one embodiment, the free alkali of crystallization formula 1 compound from the water-containing solvent mixture.In its embodiment preferred, the water-containing solvent mixture contains water and non-aqueous solvent, and wherein non-aqueous solvent is selected from: methyl alcohol, ethanol, Virahol and acetone.In another embodiment, the free alkali of formula 1 compound is from organic (C
6-C
10) crystallization, perhaps crystallization from the mixture of described organic alkane solvents in the alkane solvents.In its embodiment preferred, the crystallization method of formula 1 compound is: this compound and the heating of alkanes solvent, be cooled to the formation crystallization then earlier.In its embodiment preferred, organic (C
6-C
10) alkane solvents is selected from heptane or octane, most preferably heptane.In another embodiment as described below, free alkali prepares from the acid salt of formula 1 compound.Be appreciated that except as otherwise noted " alkane " used herein comprises the saturated monovalent hydrocarbon of straight chain, side chain or cyclic or its mixture.
In another embodiment of described method, the preparation method of the acid salt of formula 1 compound is herein: with solution-treated formula 1 compound that contains the acid in water-soluble solvent.In its embodiment preferred, described acid solution is joined in the solution that contains formula 1 compound and water.In an one embodiment preferred, described acid is phosphoric acid, L-tartrate or dibenzoyl-D-tartrate.In its particularly preferred embodiment, described acid is phosphoric acid.In its another preferred embodiment, described solvent contains ethanol.In its another embodiment preferred, aforesaid method also comprises the acid salt of separate type 1 compound.
In one embodiment, formula 1 compound prepared of described method has at least 90% purity, more preferably at least 95% purity, at least 98% purity most preferably.Specifically, the purity of formula 1 compound of method preparation of the present invention can make formula 1 compound be used to prepare the parenteral admin preparation.The requirement of parenteral admin preparation is known in the art, for example: extra high purity, particle is little in solution, aseptic preparation and remove pyrogen (referring to, Remington ' s PharmaceuticalSciences, Mack Publishing Company, Easton, Pa., 18th Edition, Gennaro compiles (1990), 1545-1580 page or leaf).
In its another embodiment preferred, aforesaid method also comprises: the free alkali that obtains formula 1 compound in the mixture of water and non-polar solvent with the acid salt of alkaline purification formula 1 compound.In an one preferred embodiment, described alkali is two subcarbonates; In particularly preferred embodiments, described two subcarbonates are salt of wormwood.In its another preferred embodiment, non-polar solvent is a methylene dichloride.In another embodiment, described method also comprises the free alkali of aforesaid crystallization formula 1 compound, and comprises aforesaid relevant other embodiment.
The invention still further relates to the method for preparation formula 2 compounds, comprising:
(a) free alkali of formula 3 compounds
With methylenation sulfonium (sulfonium methylide) ionic reaction;
(b) stop the reaction of step (a) with weakly acidic aqueous solution, and product dispensing to non-aqueous solution; With
(c) the product deprotection of step (b) is obtained formula 2 compounds;
R wherein
4Be hydroxy-protective group.
In one embodiment, aforesaid method also comprises separate type 2 compounds.In its embodiment preferred, formula 2 compounds separate with hydrate forms, more preferably with the monohydrate isolated in form.In an one embodiment, water-content is determined by the Karl-Fischer method.In an one embodiment, from the mixture that contains formula 2 compounds and solvent or solvent mixture, obtain hydrate, wherein said solvent or solvent mixture are selected from: acetone, acetone, acetone/heptane and MTBE/ heptane.In other embodiments, formula 2 compounds are with the isolated in form of acetate, L-tartrate or dibenzoyl-D-tartrate.
The present invention relates to the monohydrate of formula 2 compounds.In the preferred embodiment of aforesaid method, R
4Be carbobenzoxy-(Cbz).
In another preferred embodiment of aforesaid method, the temperature of reaction of step (a) is-80 ℃ to-45 ℃ approximately approximately.
In another embodiment of aforesaid method, the free alkali of formula 3 compounds is from the acid salt preparation of formula 3 compounds.In its embodiment preferred, acid salt is the trifluoroacetic acid additive salt.In another embodiment of aforesaid method, the acid salt of formula 3 compounds is selected from: dibenzoyl-D-tartrate, L-tartrate or phosphoric acid salt.The acid salt of compound disclosed herein is preparation in a usual manner easily.
In the embodiment of aforesaid method, the methylenation sulfonium is a dimethylated methylene base sulfonium.In its embodiment preferred, dimethylated methylene base sulfonium is by halogenide or the sulfonate and the highly basic preparation of trimethylsulfonium.In an one preferred embodiment, the halogenide of using trimethyl sulfonium, preferred bromination trimethylsulfonium.In its another preferred embodiment, the halogenide of trimethylsulfonium reacts with highly basic in inert organic solvents or its mixture.In its particularly preferred embodiment, inert organic solvents is an ether solvent, most preferably the mixture of tetrahydrofuran (THF) or tetrahydrofuran (THF) and methylene dichloride.
In one embodiment, step (c) comprises catalytic hydrogenation, wherein R
4Be benzyloxycarbonyl.In its embodiment preferred, the catalyzer of hydrogenation is a palladium/carbon catalyst.In particularly preferred embodiments, palladium/carbon catalyst is 10%Pd/C (Johnson-Matthey type A402028-10).In another embodiment of step (c), the product of step (b) is preferably used ammonium formiate, Pd/C deprotection in methyl alcohol by the catalytic transfer hydrogenation deprotection.In another embodiment, before hydrogenation, come the product of treatment step (b) with Fuller's earth (Fuller ' s earth).The suitable solvent that is used for hydrogenation is acetone, ethyl acetate, THF, MTBE, Virahol, ethanol and methyl alcohol.Preferred solvent is an acetone.
The invention still further relates to 2 '-the formula II compound of carbobenzoxy-(Cbz) protection:
It omits step (c) by aforesaid method and obtains.
The present invention relates to C-4 by oxidation-type 4 compounds " method of hydroxyl preparation formula 3 compounds,
R wherein
4Be hydroxy-protective group.
In one embodiment, oxidizing reaction is following carries out: (" DMSO ") joins in the solution that contains formula 4 compounds and solvent methyl-sulphoxide, cools off this mixture to-70 ℃ approximately, adds trifluoroacetic anhydride again, adds triethylamine then.In another embodiment, with oxalyl chloride (use or not using trimethyl silylation ethanamide), Tripyrophosphoric acid, pyridine-SO3 or diacetyl oxide activation DMSO.In its another embodiment, during adding trifluoroacetic anhydride, keep temperature of reaction at-70 ℃ to-60 ℃.In its another embodiment, described solvent is a methylene dichloride.A special advantage of aforesaid method is: in-situ activation DMSO in the presence of reactive alcohol, can avoid the formation of common impurity like this in the oxidation reaction process of activation DMSO, the oxidizing reaction that wherein activates DMSO is usually directed to described alcohol is incorporated into and contains in the solution that activates DMSO.
In one embodiment, aforesaid method also comprises the acid salt of separate type 3 compounds.In preferred embodiments, described acid salt is dibenzoyl-D-tartrate or phosphoric acid salt.In particularly preferred embodiments, the present invention relates to the preparation method of the trifluoroacetic acid additive salt of formula 3 compounds, comprising: handle formula 3 compounds, the acid salt of crystallization gained with trifluoroacetic acid;
R wherein
4Be hydroxy-protective group.
In the preferred embodiment of aforesaid method, R
4Be carbobenzoxy-(Cbz).
In another preferred embodiment of aforesaid method, acid salt is crystallization from Virahol.
In another preferred embodiment of aforesaid method, acid salt crystallization from the mixture of methylene dichloride and methyl tertiary butyl ether.
Trifluoroacetic acid additive salt with the inventive method preparation is not a pharmacologically acceptable salt, but its purity is high especially, and highly stable, thereby suitable starting raw material can be stored and transport.
In an embodiment of aforesaid method, by 2 of protection 5 compounds '-hydroxyl preparation formula 4 compounds.
In preferred embodiments, described 2 '-hydroxyl protects with carbobenzoxy-(Cbz).In another preferred embodiment, formula 5 compounds react with the benzyl chloro-formic ester of 2 molar equivalents at least.In a more preferred embodiment, be reflected in the methylene dichloride and carry out.In a more preferred embodiment, with respect to the volume of starting raw material, the volume of methylene dichloride is at least 1.5 times of excess volumes.The invention still further relates to the trifluoroacetic acid additive salt of formula 3 compounds, wherein R4 is a carbobenzoxy-(Cbz):
In its embodiment preferred, described salt has the structure shown in the formula 3a
R wherein
4Be carbobenzoxy-(Cbz).
The invention still further relates to dibenzoyl-D-tartrate, the wherein R of formula 3 compounds
4Be carbobenzoxy-(Cbz).
Except as otherwise noted, term described herein " hydroxy-protective group " comprising: the various hydroxy-protective groups that ethanoyl, carbobenzoxy-(Cbz) and those skilled in the art are familiar with, these groups can be referring to T.W.Greene, P.G.M.Wuts, " Protective Groups In Organic Synthesis, " (J.Wiley ﹠amp; Sons, 1991).Preferably, hydroxy-protective group R
4Be carbobenzoxy-(Cbz) (" CBZ ").
Except as otherwise noted, term " halogen " described herein comprises fluorine, chlorine or bromine; Term " halogenide " refers to the respective anionic of fluorine, chlorine or bromine respectively.
Except as otherwise noted, term " alkyl " described herein comprises saturated univalence hydrocarbyl of straight chain, side chain or cyclic or their mixture.
Except as otherwise noted, term " pharmacologically acceptable salt " described herein comprises acidic group or the base salt that may reside in the The compounds of this invention.Compound itself with the inventive method preparation is a basic cpd, and concrete example is suc as formula the free alkali of 1 compound, and these compounds can form multiple salt with various mineral acids and organic acid.The acid that can be used to prepare the pharmaceutically acceptable acid additive salt of the above-mentioned basic cpd of the present invention is those acid that form non-toxicity acid salt, the example of described salt is for containing pharmaceutically acceptable anionic salt, hydrochloride for example, hydrobromate, hydriodate, nitrate, vitriol, hydrosulfate, phosphoric acid salt, acid phosphate, Yi Yansuan salt, acetate, lactic acid salt, salicylate, citrate, the acid citrate, tartrate, pantothenate, bitartrate, ascorbate salt, succinate, maleate, gentisate, fumarate, gluconate, glucaronate, saccharate (saccharate), formate, benzoate, glutaminate, mesylate, esilate, benzene sulfonate, tosilate and pamoate are [promptly, 1,1 '-methylene radical-two-(2-hydroxyl-3-naphthoate)].Except the above-mentioned acid of mentioning, the compound that contains amino for preparing with the inventive method can also form pharmacologically acceptable salt with each seed amino acid.
Except as otherwise noted, treatment or prevention infectation of bacteria or the protozoal infections that provides in the methods of the invention is provided term " treatment " used herein.
The present invention includes The compounds of this invention, its pharmacologically acceptable salt, wherein one or more hydrogen, carbon, nitrogen or other atom are replaced by its isotropic substance.Such compound can be used as research and diagnostic tool in the metabolism pharmacokinetic studies with in conjunction with test.
Summary of the invention
Can carry out method of the present invention according to the description of following scheme 1-4 and back, except as otherwise noted, substituent R in the following scheme
3, R
4, R
8And R
15As above definition.
Scheme 1
Scheme 2
Scheme 3
Formula 4 compounds as the inventive method starting raw material prepare from formula 5 compounds (being that R4 is the compound of hydrogen) easily, referring to WO 98/56802 and US4, and 328,334,4,474,768 and 4,517,359, the full text of all these documents is hereby incorporated by.
The above-mentioned scheme that provides only is to illustrate for example, and will be described in further detail below, and will be for a more detailed description in an embodiment.In scheme 1, the epoxide of formula 2 changes the amine of an accepted way of doing sth 1, wherein R
3For-CH
2NR
15R
8, R wherein
15And R
8As mentioned above.In the most preferred embodiment of the present invention, described amine is Tri N-Propyl Amine, i.e. R
8Be n-propyl, R
15Be hydrogen.
For preparation formula 1 compound, preferably, in suitable solvent (for example Virahol or contain the ORGANIC SOLVENT MIXTURES of Virahol), use formula HNR
15R
8Compound treatment formula 2 compounds, wherein R
15And R
8, as above definition is preferably reacted at about 40 ℃ to about 95 ℃.Most preferred temperature of reaction is about 50 ℃ to about 55 ℃, but also can use higher temperature, for example 76 ℃.React most preferred pressure near normal pressure, react yet also can pressurize.
At an aforesaid method of the open loop of formula 2 epoxide (referring to WO 98/56802; embodiment 48,50, and 51 and 70) in; 2 '-hydroxyl is protected, and preparation formula 1 compound (perhaps formula 1a compound) needs the amination of epoxide and the hydrolysis of blocking group to carry out simultaneously.This method is not a preferable methods, is invalid because be hydrolyzed during the epoxide open loop step, and owing to the not existence of hydrolysising protection group and other impurity, separate type 1 compound becomes more difficult.In another preceding method, formula 2 compounds (wherein 2 '-hydroxyl is not protected) and pure alkylamine promptly react without organic solvent.In this case, the normal boiling point temperature (about 48 ℃) that is reflected at Tri N-Propyl Amine is slowly carried out.Therefore,, be reflected to add to depress and carry out in order at high temperature to produce, for industrial production be disadvantageous (referring to, WO 98/56802, embodiment 8 (preparation 2), productive rate 11%).In addition, need applications catalyst in the reaction.The applicant finds: the boiling point of the mixture of Tri N-Propyl Amine and Virahol under normal pressure is about 76 ℃, makes reaction have high productive rate (greater than 85%), and temperature of reaction is about 50-55 ℃, does not need application of pressure reactor or catalyzer.Applicant's method provides high yield (85%), the product purity that obtains than existing method is higher, and the free alkali form and the hydrochlorate of formula 1 compound all have multiple crystallization method, have obtained highly purified formula 1 compound, and its purity can be used to prepare parenteral formulation.
In embodiment 2, formula 2 compounds can be prepared as follows: approximately-80 to-45 ℃ temperature approximately with methylenation sulphur (sulfur methylide) processing formula 3 compounds, then with ordinary method remove 2 '-blocking group, obtain formula 2 compounds.Preferably, the starting raw material of embodiment 2 methods is the trifluoroacetic acid additive salt of formula 3 compounds, at first is converted into free alkali form, is cooled to-70 ℃ low temperature approximately then, and the cryogenic fluid with methylenation sulphur reacts then.Preferably, methylenation sulphur is dimethylated methylene base sulfonium, for example (CH
3)
2S
+CH
2 -, it can prepare with ordinary method, for example: at ether solvents THF or at CH for example
2Cl
2, DMF or DMSO or in the mixture of above-mentioned two or more solvents, with activator (for example potassium hydroxide, tert.-butoxy potassium, tert.-butoxy sodium, oxyethyl group potassium, Sodium Ethoxide, hexamethyldisilane potassium (potassium hexamethyldisilazide, KHMDS) or sodium methoxide, preferred tertiary butoxy potassium wherein) handle trimethylammonium sulfonium salt, for example (CH
3)
3SX, wherein X is halogen (preferred bromine) or sulfonate radical, more preferably bromination trimethylsulfonium.Remove blocking group with usual manner, for example applied catalysis hydrogenation mode, wherein R
4Be CBZ.
In embodiment 3, can be with continuation method preparation 4 " ketone in single container.In the first step of this method, 2 '-hydroxyl selective protection in a usual manner, preferably in methylene dichloride, handle R with chloroformic acid benzyl ester
4For 2 of formula 5 compounds of hydrogen '-hydroxyl, obtain R
4Formula 4 compounds for carbobenzoxy-(Cbz) (" CBZ ").Preferably, use the chloroformic acid benzyl ester of at least 2 molar equivalents, so that guarantee 2 '-hydroxyl becomes the form of protecting completely.Be solvent preferably with methylene dichloride.When wherein reacting, the volume of methylene dichloride is at least 15 times of starting raw material volume, has therefore reduced the formation of two-CBZ impurity.R wherein
4For formula 4 compounds of CBZ can its dibenzoyl-D-tartrate isolated in form, removed like this potential two-CBZ impurity.Yet the water extraction treatment method of formula 4 compounds is not preferred, owing to there is the benzylamine that is obtained by benzyl chlorine (being decomposed to form by chloroformic acid benzyl ester) aminoalkyl formula 4 compounds, therefore isolating product is unsettled.So, after the protection step, preferably make reaction mixture directly enter second step, and do not need separate type 4 compounds.Described second step can with the same container of first step in carry out, it comprises oxidation 4 " hydroxyl obtain formula 3 compounds 4 "-ketone group.Preferably, oxidizing reaction is the oxidation of aforesaid activation DMSO, promptly carries out at low temperatures, for example carries out under-60 to-70 ℃, it comprises that original position carries out the activation of DMSO: trifluoroacetic anhydride is joined in the cooling solution of described compound in DMSO, add triethylamine then.Then reaction mixture is added to the water, is warmed to room temperature gradually.Preferably, wash the solution that mixture obtains formula 3 compounds with water.
The trifluoroacetate of formula 3 compounds can prepare like this: the reaction mixture that washes oxidation step with water, add trifluoroacetic acid subsequently, add to be fit to salt crystalline solvent then, for example Virahol or the mixture formed by methylene dichloride and methyl tertiary butyl ether (" MTBE ").Also can prepare other acid salt in the usual way, for example dibenzoyl-D-tartrate and phosphoric acid salt.Described dibenzoyl-D-tartrate and phosphoric acid salt are useful to method of the present invention, but compare less better with trifluoroacetic acid.
As implement shown in the scheme 4, generally speaking, the present invention relates to the method for two stage preparation formulas, 1 compound, in the fs, formula 3 compounds are by single vessel process preparation, comprise: formula 5 compounds carry out 2 '-the carbobenzoxy-(Cbz) protection of hydroxyl obtains formula 4 compounds, 4 compounds of direct oxidation formula then 4 " hydroxyl obtains the ketone of formula 3 compounds, and preferable separation becomes its trifluoroacetic acid additive salt form; In subordinate phase; the free alkali of wushu 3 compounds (preferably from its trifluoroacetate preparation) is transformed into 4 " formula 2 compounds of epoxide; remove 2 '-blocking group is reduced into 2 '-hydroxyl, in containing the mixture of Virahol, open epoxide and obtain formula 1 compound with amine.
Scheme 4
The fs subordinate phase
Compound itself with the inventive method preparation is an alkalescence, and it can form multiple different salt with various mineral acids and organic acid.Though in order to be applied to these salt of Mammals must be pharmaceutically useful, but in fact usually need from reaction mixture, to isolate compound by the non-pharmaceutical salts form of the inventive method preparation, handling with alkaline reagents simply then makes it be transformed into free alkali compound, for use in subsequent reaction, perhaps be used to prepare the pharmaceutically acceptable acid additive salt.Can be at hydrosolvent medium or in appropriate organic solvent, the usefulness selected mineral acid or the organic acid of equivalent is basically handled this alkali cpd, prepares the acid salt by the alkali cpd of the inventive method preparation easily.Carefully, obtain needed solid salt easily after the solvent evaporation.Suitable mineral acid or organic acid can be joined also that precipitation obtains needed salt in the organic solvent solution of this free alkali.With formula 1 compound of the inventive method preparation and pharmacologically acceptable salt (after this claiming " active compound ") thereof can oral administration, parenteral, part or rectum administration be used for the treatment of infectation of bacteria or protozoal infections.
In general, the best dosage of active compound is the about 200mg/kg body weight/day of about 0.2-(mg/kg/ days), divide single or multiple administration (being 1-4 time/day), though different according to selected route of administration with the species of patient of being treated, body weight and healthy state, need do necessary adjustment to dosage; Yet, most preferably use about 4mg/kg/ days-dosage level of Yue 50mg/kg/ days.According to the kinds of the Mammals of being treated, fish or birds, these animals and at interval, can make adjustment to dosage to the individual reaction of described medicine and selected types of drug preparations, administration time.In some cases, the dosage level that is lower than above-mentioned scope lower limit may be also higher than suitable dose, and in other cases, can use the dosage higher than above-mentioned scope and also can not produce any toxic side effect, condition is at first big dosage like this to be divided into some low dose of whole day administrations.
These active compounds can be individually dosed according to above-mentioned approach, also can with pharmaceutically acceptable carrier or thinner according to above-mentioned approach combination medicine-feeding, such administration can single-dose, also can multiple dosing.More particularly, described active compound can be with multiple different formulation administration, and promptly they can make up with formulation administrations such as tablet, capsule, lozenge (lozenges), lozenge (troches), boiled sweet hard candies, pulvis, sprays, emulsifiable paste, ointment (salves), suppository, gel (jellies), gel (gels), paste, lotion, ointment, aqeous suspension, injection solution, elixir and syrups with various pharmaceutically acceptable carrier.Described carrier comprises solid diluent or weighting agent, aseptic aqueous medium and various non-toxic organic solvent etc.And combination of oral medication can carry out dulcification and/or flavoring suitably.As a rule, in these formulations, the content of active compound is about 5.0% to about 70% weight.
Just oral, can for example starch (preferred W-Gum, yam starch or tapioca (flour)), alginic acid and some composition silicate be used and combined utilization granulation binders for example polyvinylpyrrolidone, sucrose, gelatin and gum arabic with various disintegrating agents the tablet that contains various vehicle (for example Microcrystalline Cellulose, Trisodium Citrate, lime carbonate, Lin Suanergai and glycine).In addition, lubricant (for example Magnesium Stearate, sodium lauryl sulphate and talcum powder) is useful to compressing tablet usually.The solids composition of similar type can also be as the weighting agent of gelatine capsule; Preferable material also comprises lactose or toffee and high molecular weight polyethylene glycol in this respect.When oral needs are used water suspending agent and/or elixir, can mix active compound with various sweeting agents or correctives, tinting material or dyestuff, if desired, can also combined utilization emulsifying agent and/or suspension agent and for example water, ethanol, propylene glycol, glycerine and various similar combination thereof of thinner.
With regard to parenteral admin, can the solution of application of active compound in sesame oil or peanut oil or aqueous propylene glycol.If desired, can cushion suitably, and at first liquid diluent such as is adjusted at the state that oozes the described aqueous solution.These aqueous solution are suitable for intravenous injection.Oily solution is suitable for intra-articular injection, intramuscular injection and subcutaneous injection.The preparation of all these sterile solutions is finished by standard pharmaceutical technology well known by persons skilled in the art easily.
In addition, also can be the The compounds of this invention topical, this can carry out with formulations such as emulsifiable paste, gel (jellies), gel (gels), paste, patch and ointment according to the standard drug standard.
In order to deliver medicine to the animal beyond the people, poultry or livestock for example can be active compound with the animal-feed form administration, perhaps with drencs composition (drench composition) form administration.
This active compound also can the administration of liposome release system, for example little unilamellar vesicle (vesicles), big unilamellar vesicle or multilamellar vesicle form.Can prepare liposome from various phospholipids, for example from cholesterol, stearylamine or Yelkin TTS preparation.
This active compound can also with for example target medicine carrier coupling of soluble polymer.Described polymkeric substance can comprise polyvinylpyrrolidone, pyran co-polymer, poly-hydroxypropylmethyl acrylamide phenyl, poly-hydroxyethyl asparamide-phenol or the polyethylene oxide-polylysin that is replaced by palmitoyl.And this active compound can be coupled to for example crosslinked or amphiphilic block copolymer of poly(lactic acid), polyglycolic acid, polylactic acid-polyglycolic acid multipolymer, poly-epsilon-caprolactone, polyhydroxybutyrate, poe, polyacetal, poly-dihydroxyl pyrans, polybutylcyanoacrylate and hydrogel of Biodegradable polymer that a class is used for controlled release drug.
The following example further illustrates method of the present invention and intermediate, is appreciated that the detail that the invention is not restricted to the following example.
Embodiment 1
(2R, 3S, 4R, 5R, 8R, 10R, 11R, 12S, 13S, 14R)-13-[(2,6-dideoxy-3-C-methyl-3-O-methyl-α-L-nuclear-own pyrans glycosyl (hexopyranosyl)) oxygen]-2-ethyl-3,4,10-trihydroxy--3,5,8,10,12,14-vegolysen 1-[[3,4,6-three deoxidations-3-(dimethylamino)-2-O-[(phenyl methoxyl group) carbonyl]-β-D-wood-own pyrans glycosyl] oxygen]-preparation of 1-oxa--6-nitrogen heterocyclic pentadecane-15-ketone
Toward being cooled to 0-5 ℃, 25kg (2R, 3S, 4R, 5R, 8R, 10R, 11R, 12S, 13S, 14R)-13-[(2,6-dideoxy-3-C-methyl-3-O-methyl-α-L-nuclear-own pyrans glycosyl) oxygen]-2-ethyl-3,4,10-trihydroxy--3,5,8,10,12,14-vegolysen 1-[[3,4,6-three deoxidations-3-(dimethylamino)-β-D-wood-own pyrans glycosyl] oxygen]-add methylene dichloride (25L) solution of 13.7kg chloroformic acid benzyl ester in methylene dichloride (425L) solution of 1-oxa--6-nitrogen heterocyclic pentadecane-15-ketone, the control rate of addition with holding temperature below 5 ℃.Under this temperature, stirred the gained mixture 3 hours, be concentrated into 148L then, obtain containing the have an appointment drying solution of 26.6kg (90%) product and (use HPLC-Waters Symmetry C8,15cm * 3.9mm I.D. post, with 25mM potassium phosphate buffer (pH 7.5): acetonitrile: methyl alcohol (35: 50: 15) is moving phase, flow velocity 2.0ml/min, Electrochemical Detection, retention time=8.2 minute).This mixture is directly used among the embodiment 2.
Embodiment 2
(2R, 3S, 4R, 5R, 8R, 10R, 11R, 12S, 13S, 14R)-13-[(2,6-dideoxy-3-C-methyl-3-O-methyl-α-L-nuclear-own pyrans glycosyl) oxygen]-2-ethyl-3,4,10-trihydroxy--3,5,8,10,12,14-vegolysen 1-[[3,4,6-three deoxidations-3-(dimethylamino)-2-O-[(phenyl methoxyl group) carbonyl]-β-D-wood-own pyrans glycosyl] oxygen]-preparation of the two trifluoroacetates of 1-oxa--6-nitrogen heterocyclic pentadecane-15-ketone
In the solution of embodiment 1 gained, add 58.6kg methyl-sulphoxide (" DMSO "), be cooled to-70 ℃ then.Keeping-70 to-60 ℃ during, add the 16kg trifluoroacetic anhydride, mixture was stirred 30 minutes, add the 17.2kg triethylamine then, gained mixture restir 30 minutes.Reaction mixture is joined in the 175L water, be warmed to room temperature gradually, layering.Organic layer is concentrated into about 100L with 170L water washing twice.Then, add the 7.8kg trifluoroacetic acid, add the 236L Virahol again, the enriched mixture crystallization goes out 29.5kg (87.9%) product, and measuring purity with HPLC is 98%.
Analytical data: mp=187-192 ℃
Ultimate analysis (C
49H
76F
6N
2O
18Calculated value: C, 53.74; H, 6.99; F, 10.41; N, 2.56; Measured value: C, 53.87; H, 6.99; F, 10.12; N, 2.59.
HPLC system: identical with embodiment 1; Retention time=9.5 minute.
X-light powdery diffractometry (d spacing): 6.3,8.3,8.8,9.4,10.8,11.8,12.6,13.0,14.3,15.4,15.9,16.4,17.1,17.4,17.8,18.1,19.1,19.8,20.4,21.1,21.5,21.7,22.8,23.4,24.0.
Embodiment 3
(2R, 3S, 4R, 5R, 8R, 10R, 11R, 12S, 13S, 14R)-2-ethyl-3,4,10-trihydroxy--13-[[(3S, 4S, 6R, 8R)-and 8-methoxyl group-4,8-dimethyl-1,5-dioxo spiro [2.5] suffering-6-yl] oxygen] 3,5,8,10,12,14-vegolysen 1-[[3,4,6-three deoxidations-3-(dimethylamino)-2-O-[(phenyl methoxyl group) carbonyl]-β-D-wood-own pyrans glycosyl] oxygen]-preparation of 1-oxa--6-nitrogen heterocyclic pentadecane-15-ketone
(a) solution of product in 327 liters of methylene dichloride of the solution-treated 109kg embodiment 2 of usefulness 27.5kg salt of wormwood in 327L water.Layering with 327 liters of washed with dichloromethane water layers, merges organic layer, and drying is evaporated to about 327L, is cooled to-70 ℃.
(b) suspension of 29.7g bromination trimethylsulfonium in 436L tetrahydrofuran (THF) (" THF ") is evaporated to about 170L at one independently in the container, is cooled to-12 ℃, with 36.8kg tert.-butoxy potassium-10 to-15 ℃ Temperature Treatment 75 minutes.This mixture is joined in the dichloromethane solution of step (a) with about 30 minutes time then, holding temperature is warmed to-65 ℃ to the mixture that obtains at-70 to-80 ℃ simultaneously, stirs at least 1 hour.Then this mixture is joined 55.4kg ammonium chloride in the solution of 469 premium on currency.Stirred this mixture 15 minutes 15-25 ℃ temperature, layering with 360L washed with dichloromethane water layer, merges organic layer, is evaporated to about 227L.In the gained mixture, add 750L acetone.Then, mixture is evaporated to 227 liters, this solution contains the 70.1kg that has an appointment (80%) title product, and (the HPLC-HPLC system: MetaSil AQ C18 post is (from MetaChem, part number 0520-250X046), 50mM potassium phosphate buffer (pH 8.0): acetonitrile: methyl alcohol (30: 60: 10) is mobile phase, 1.0ml/min flow velocity, Electrochemical Detection. retention time=31.1 minute).This mixture directly applies to
Embodiment 4.
Embodiment 4
(2R, 3S, 4R, 5R, 8R, 10R, 11R, 12S, 13S, 14R)-2-ethyl-3,4,10-trihydroxy--13-[[(3S, 4S, 6R, 8R)-and 8-methoxyl group-4,8-dimethyl-1,5-dioxo spiro [2.5] suffering-6-yl] oxygen]-3,5,8,10,12,14-vegolysen 1-[[3,4,6-three deoxidations-3-(dimethylamino)-α-D-wood-own pyrans glycosyl] oxygen]-preparation of 1-oxa--6-nitrogen heterocyclic pentadecane-15-ketone
The solution that contains embodiment 3 products is mixed with 11kg activated carbon, 17.5kg10% palladium-carbon (Johnson-Matthey type A402028-10) and 637L acetone, under 20-25 ℃ and 50psi pressure, finish until reaction, then filtration with hydrogen treat gained mixture.Filtrate is concentrated into about 350L, adds 1055L water with time of 90 minutes then.Filter and collect crystallized product, with the mixture washing of 132 premium on currency and 45 liters of acetone, dry back obtains the title epoxide (measuring water content with the Karl-Fischer method) of 57.5kg (94.4%) monohydrate form.
Analytical data: HPLC system: the same with embodiment 3; Retention time=13.3 minute.
X-light powdery diffractometry (d spacing): 6.0,8.5,9.4,11.9,12.7,13.4,15.2,16.9,17.5,18.0,18.9,19.4,19.9,20.7,21.2,21.6,22.8.
Embodiment 5
(2R, 3S, 4R, 5R, 8R, 10R, 11R, 12S, 13S, 14R)-13-[(2,6-dideoxy-3-C-methyl-3-O-methyl-4-C-[(Propylamino) methyl]-α-L-nuclear-own pyrans glycosyl) oxygen-2-ethyl-3,4,10-trihydroxy--3,5,8,10,12,14-vegolysen 1-[[3,4,6-three deoxidations-3-(dimethylamino)-α-D-wood-own pyrans glycosyl] oxygen]-preparation of 1-oxa--6-nitrogen heterocyclic pentadecane-15-ketone Diphosphonate
The epoxide monohydrate of 56kg embodiment 4 and 280L Virahol and 108.2kg Tri N-Propyl Amine are merged.Heated this mixture 30 hours down at 50-55 ℃.Vacuum concentration is to about 112 liters then.In this enriched material, add 560L ethanol and 44.8L water.With about 2 hours time drip in this mixture 16.8kg phosphoric acid in 252 liters of alcoholic acid solution with crystallized product.The suspension that stirring obtains 18 hours, filtering mixt, with 28 liters of washing with alcohol solids, desciccate obtains 64.6kg (88%) title compound (HPLC-HPLC system: YMC-Pack Pro C18 (YMC Inc.Part#AS-12S03-1546WT), with 50mM dipotassium hydrogen phosphate damping fluid (pH 8.0): acetonitrile: methyl alcohol (61: 21: 18) is made mobile phase, flow velocity 1.0ml/min, electrochemical detector.Retention time=26.4 minute).
Embodiment 6
(2R, 3S, 4R, 5R, 8R, 10R, 11R, 12S, 13S, 14R)-13-[(2,6-dideoxy-3-C-methyl-3-O-methyl-4-C-[(third amino) methyl]-α-L-nuclear-own pyrans glycosyl) oxygen-2-ethyl-3,4,10-trihydroxy--3,5,8,10,12,14-vegolysen 1-[[3,4,6-three deoxidations-3-(dimethylamino)-β-D-wood-own pyrans glycosyl] oxygen]-preparation of 1-oxa--6-nitrogen heterocyclic pentadecane-15-ketone free alkali
The product of 64.6kg embodiment 5 is mixed with 433L methylene dichloride, 433L water and 27.6kg salt of wormwood, stirred this mixture 30 minutes, isolate organic layer, water layer 32L washed with dichloromethane.Merge organic layer, filter and make it clarification, be evaporated to about 155L.Add the 386L heptane in this enriched material, evaporating solns is cooled to 20-25 ℃ to produce crystallization to about 155L.Stirred this mixture 6 hours, solid collected by filtration is used the 110L heptane wash, and drying obtains 40.3kg (77%) title compound (HPLC; With system similarly to Example 5; Retention time=26.4 minute).
Claims (7)
2. the process of claim 1 wherein R
4Be carbobenzoxy-(Cbz).
3. the process of claim 1 wherein the Virahol crystallization of described acid salt.
4. the process of claim 1 wherein described acid salt crystalline mixture with methylene dichloride and methyl tertiary butyl ether.
5. the trifluoroacetic acid additive salt of following formula 3 compounds,
R wherein
4Be carbobenzoxy-(Cbz).
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